tbuckley/cabot-search huggingface dataset:
Nonoperative vs Operative Management of Uncomplicated Acute Appendicitis
Authors: Rodrigo Moises de Almeida Leite, Dong Joo Seo, Barbara Gomez-Eslava, Sigma Hossain, Arnaud Lesegretain, Alexandre Venâncio de Souza, Camden Phillip Bay, Bruno Zilberstein, Evaldo Marchi, Rogerio Bonassi Machado, Leandro Cardoso Barchi, Rocco Ricciardi
Journal: JAMA Surgery (2022)

Appendectomy remains the standard of care for uncomplicated acute appendicitis despite several randomized clinical trials pointing to the safety and efficacy of nonoperative management of this disease. A meta-analysis of randomized clinical trials may contribute to the body of evidence and help surgeons select which patients may benefit from surgical and nonsurgical treatment.
Demographic and Regional Trends of Heart Failure–Related Mortality in Young Adults in the US, 1999-2019
Authors: Vardhman Jain, Abdul Mannan Khan Minhas, Alanna A. Morris, Stephen J. Greene, Ambarish Pandey, Sadiya S. Khan, Gregg C. Fonarow, Robert J. Mentz, Javed Butler, Muhammad Shahzeb Khan
Journal: JAMA Cardiology (2022)

There are limited data on mortality trends in young adults with heart failure (HF).To study the trends in HF-related mortality among young adults.This retrospective cohort analysis used mortality data of young adults aged 15 to 44 years with HF listed as a contributing or underlying cause of death in the US Centers for Disease Control and Prevention Wide-Ranging Online Data for Epidemiologic Research database from January 1999 to December 2019. Analysis took place in October 2021.Age 15 to 44 years with HF listed as a contributing or underlying cause of death.HF-related age-adjusted mortality rates (AAMR) per 100 000 US population stratified by sex, race and ethnicity, and geographic areas.Between 1999 and 2019, a total of 61 729 HF-related deaths occurred in young adults. Of these, 38 629 (62.0%) were men and 23 460 (38.0%) were women, and 22 156 (35.9%) were Black, 6648 (10.8%) were Hispanic, and 30 145 (48.8%) were White. The overall AAMR per 100 000 persons for HF in young adults increased from 2.36 in 1999 to 3.16 in 2019. HF mortality increased in young men and women, with men having higher AAMRs throughout the study period. AAMR increased for all race and ethnicity groups, with Black adults having the highest AAMRs (6.41 in 1999 and 8.58 in 2019). AAMR for Hispanic adults and White adults increased from 1.62 to 2.04 and 1.83 to 2.45 over the same time period, respectively. Across most demographic and regional subgroups, HF-related mortality stayed stable or decreased between 1999 and 2012, followed by an increase between 2012 and 2019. There were significant regional differences in the burden of HF-related mortality, with states in the upper 90th percentile of HF-related mortality (Oklahoma, South Carolina, Louisiana, Arkansas, Alabama, and Mississippi) having a significantly higher mortality burden compared with those in the bottom tenth percentile.Following an initial period of stability, HF-related mortality in young adults increased from 2012 to 2019 in the United States. Black adults have a 3-fold higher AAMR compared with White adults, with significant geographic variation. Targeted health policy measures are needed to address the rising burden of HF in young adults, with a focus on prevention, early diagnosis, and reduction in disparities.
The Promise of Service-Enriched, Hotel-Based Housing as an Alternative to Congregate Shelters for High-Need Persons Experiencing Homelessness
Authors: Joel C. Cantor, Emmy Tiderington
Journal: JAMA Network Open (2022)

Mark D. Fleming, PhD, MS; Jennifer L. Evans, MS; Dave Graham-Squire, PhD; Caroline Cawley, MPH; Hemal K. Kanzaria, MD, MSc; Margot B. Kushel, MD; Maria C. Raven, MD, MPH, MS
A Fork in the Road to Health Equity—Lesson From Odetta
Authors: Khadijah Breathett
Journal: JAMA Network Open (2022)

Thomas M. Cascino, MD, MS; Sriram Somanchi, PhD; Monica Colvin, MD; Grace S. Chung, MPH; Alexander A. Brescia, MD, MSc; Michael Pienta, MD; Michael P. Thompson, PhD; James W. Stewart II, MD; Devraj Sukul, MD, MSc; Daphne C. Watkins, PhD; Francis D. Pagani, MD, PhD; Donald S. Likosky, PhD; Keith D. Aaronson, MD, MS; Jeffrey S. McCullough, PhD
Redifferentiation Therapy—Returning to Our Roots in a Post–Kinase Inhibitor World
Authors: Maria E. Cabanillas, Naifa L. Busaidy, Steven I. Sherman
Journal: Clinical Cancer Research (2022)

Summary Radioactive iodine (RAI) treatment is an effective treatment for differentiated thyroid cancer (DTC); however, many patients are refractory. Using targeted drugs to reinduce RAI sensitivity (“redifferentiation therapy”) has long been sought after as the holy grail in endocrine oncology. See related article by Weber et al., p. 4194
Antibody-mediated prevention of vaginal HIV transmission is dictated by IgG subclass in humanized mice
Authors: Jacqueline M. Brady, Meredith Phelps, Scott W. MacDonald, Evan C. Lam, Adam Nitido, Dylan Parsons, Christine L. Boutros, Cailin E. Deal, Wilfredo F. Garcia-Beltran, Serah Tanno, Harini Natarajan, Margaret E. Ackerman, Vladimir D. Vrbanac, Alejandro B. Balazs
Journal: Science Translational Medicine (2022)

HIV broadly neutralizing antibodies (bNAbs) are capable of both blocking viral entry and driving innate immune responses against HIV-infected cells through their Fc region. Vaccination or productive infection results in a polyclonal mixture of class-switched immunoglobulin G (IgG) antibodies composed of four subclasses, each encoding distinct Fc regions that differentially engage innate immune functions. Despite evidence that innate immunity contributes to protection, the relative contribution of individual IgG subclasses is unknown. Here, we used vectored immunoprophylaxis in humanized mice to interrogate the efficacy of individual IgG subclasses during prevention of vaginal HIV transmission by VRC07, a potent CD4-binding site–directed bNAb. We find that VRC07 IgG2, which lacks Fc-mediated functionality, exhibited substantially reduced protection in vivo relative to other subclasses. Low concentrations of highly functional VRC07 IgG1 yielded substantial protection against vaginal challenge, suggesting that interventions capable of eliciting modest titers of functional IgG subclasses may provide meaningful benefit against infection.
Association of a common genetic variant with Parkinson’s disease is mediated by microglia
Authors: Rebekah G. Langston, Alexandra Beilina, Xylena Reed, Alice Kaganovich, Andrew B. Singleton, Cornelis Blauwendraat, J. Raphael Gibbs, Mark R. Cookson
Journal: Science Translational Medicine (2022)

Studies of multiple neurodegenerative disorders have identified many genetic variants that are associated with risk of disease throughout a lifetime. For example, Parkinson’s disease (PD) risk is attributed in part to both coding mutations in the leucine-rich repeat kinase 2 ( LRRK2 ) gene and to a common noncoding variation in the 5′ region of the LRRK2 locus, as identified by genome-wide association studies (GWAS). However, the mechanisms linking GWAS variants to pathogenicity are largely unknown. Here, we found that the influence of PD-associated noncoding variation on LRRK2 expression is specifically propagated through microglia and not by other cell types that express LRRK2 in the human brain. We find microglia-specific regulatory chromatin regions that modulate the LRRK2 expression in human frontal cortex and substantia nigra and confirm these results in a human-induced pluripotent stem cell–derived microglia model. We showed, using a large-scale clustered regularly interspaced short palindromic repeats interference (CRISPRi) screen, that a regulatory DNA element containing the single-nucleotide variant rs6581593 influences the LRRK2 expression in microglia. Our study demonstrates that cell type should be considered when evaluating the role of noncoding variation in disease pathogenesis and sheds light on the mechanism underlying the association of the 5′ region of LRRK2 with PD risk.
Histamine production by the gut microbiota induces visceral hyperalgesia through histamine 4 receptor signaling in mice
Authors: Giada De Palma, Chiko Shimbori, David E. Reed, Yang Yu, Virginia Rabbia, Jun Lu, Nestor Jimenez-Vargas, Jessica Sessenwein, Cintya Lopez-Lopez, Marc Pigrau, Josue Jaramillo-Polanco, Yong Zhang, Lauren Baerg, Ahmad Manzar, Julien Pujo, Xiaopeng Bai, Maria Ines Pinto-Sanchez, Alberto Caminero, Karen Madsen, Michael G. Surette, Michael Beyak, Alan E. Lomax, Elena F. Verdu, Stephen M. Collins, Stephen J. Vanner, Premysl Bercik
Journal: Science Translational Medicine (2022)

The gut microbiota has been implicated in chronic pain disorders, including irritable bowel syndrome (IBS), yet specific pathophysiological mechanisms remain unclear. We showed that decreasing intake of fermentable carbohydrates improved abdominal pain in patients with IBS, and this was accompanied by changes in the gut microbiota and decreased urinary histamine concentrations. Here, we used germ-free mice colonized with fecal microbiota from patients with IBS to investigate the role of gut bacteria and the neuroactive mediator histamine in visceral hypersensitivity. Germ-free mice colonized with the fecal microbiota of patients with IBS who had high but not low urinary histamine developed visceral hyperalgesia and mast cell activation. When these mice were fed a diet with reduced fermentable carbohydrates, the animals showed a decrease in visceral hypersensitivity and mast cell accumulation in the colon. We observed that the fecal microbiota from patients with IBS with high but not low urinary histamine produced large amounts of histamine in vitro. We identified Klebsiella aerogenes , carrying a histidine decarboxylase gene variant, as a major producer of this histamine. This bacterial strain was highly abundant in the fecal microbiota of three independent cohorts of patients with IBS compared with healthy individuals. Pharmacological blockade of the histamine 4 receptor in vivo inhibited visceral hypersensitivity and decreased mast cell accumulation in the colon of germ-free mice colonized with the high histamine-producing IBS fecal microbiota. These results suggest that therapeutic strategies directed against bacterial histamine could help treat visceral hyperalgesia in a subset of patients with IBS with chronic abdominal pain.
Long covid: Hair loss and sexual dysfunction are among wider symptoms, study finds
Authors: Jacqui Wise
Journal: BMJ (2022)

<h3>Objective</h3> To synthesise the available scientific evidence on the effects of combined exercise on glycaemic control, weight loss, insulin sensitivity, blood pressure and serum lipids among patients with type 2 diabetes (T2D) and concurrent overweight/obesity. <h3>Design and sample</h3> PubMed, EMBASE, Web of Science, the Cochrane library, WANFANG, CNKI, SinoMed, OpenGrey and ClinicalTrials.gov were searched from inception through April 2020 to identify randomised controlled trials (RCTs) that reported the effects of combined exercise in individuals with T2D and concurrent overweight/obesity. <h3>Methods</h3> Quality assessment was performed using the Cochrane Collaboration’s risk of bias tool. The mean difference (MD) with its corresponding 95% CI was used to estimate the effect size. Meta-analysis was performed using Review Manager V.5.3. <h3>Results</h3> A total of 10 RCTs with 978 participants were included in the meta-analysis. Pooled results demonstrated that combined exercise significantly reduced haemoglobin A1c (MD=−0.16%, 95% CI: −0.28 to −0.05, p=0.006); body mass index (MD=−0.98 kg/m<sup>2</sup>, 95% CI: −1.41 to −0.56, p&lt;0.001); homeostasis model assessment of insulin resistance (MD=−1.19, 95% CI: −1.93 to −0.46, p=0.001); serum insulin (MD=−2.18 μIU/mL, 95% CI: −2.99 to −1.37, p&lt;0.001) and diastolic blood pressure (MD=−3.24 mm Hg, 95% CI: −5.32 to −1.16, p=0.002). <h3>Conclusions</h3> Combined exercise exerted significant effects in improving glycaemic control, influencing weight loss and enhancing insulin sensitivity among patients with T2D and concurrent overweight/obesity.
Antihypertensive drugs and brain function: mechanisms underlying therapeutically beneficial and harmful neuropsychiatric effects
Authors: Carla Carnovale, Cristiana Perrotta, Sara Baldelli, Dario Cattaneo, Cristina Montrasio, Silvia S Barbieri, Giulio Pompilio, Chiara Vantaggiato, Emilio Clementi, Marco Pozzi
Journal: Cardiovascular Research (2022)

Abstract A bidirectional relationship exists between hypertension and psychiatric disorders, including unipolar and bipolar depression, anxiety, post-traumatic stress disorder (PTSD), psychosis, schizophrenia, mania, and dementia/cognitive decline. Repurposing of antihypertensive drugs to treat mental disorders is thus being explored. A systematic knowledge of the mechanisms of action and clinical consequences of the use of antihypertensive agents on neuropsychiatric functions has not been achieved yet. In this article, we review the putative role of antihypertensive agents in psychiatric disorders, discuss the targets and mechanisms of action, and examine how and to what extent specific drug classes/molecules may trigger, worsen, or mitigate psychiatric symptoms. In addition, we review pharmacokinetics (brain penetration of drugs) and pharmacogenetics data that add important information to assess risks and benefits of antihypertensive drugs in neuropsychiatric settings. The scientific literature shows robust evidence of a positive effect of α1 blockers on PTSD symptoms, nightmares and sleep quality, α2 agonists on core symptoms, executive function, and quality of life in Attention-Deficit/Hyperactivity Disorder, PTSD, Tourette’s syndrome, and β blockers on anxiety, aggression, working memory, and social communication. Renin-angiotensin system modulators exert protective effects on cognition, depression, and anxiety, and the loop diuretic bumetanide reduced the core symptoms of autism in a subset of patients. There is no evidence of clear benefits of calcium channel blockers in mood disorders in the scientific literature. These findings are mainly from preclinical studies; clinical data are still insufficient or of anecdotal nature and seldom systematic. The information herewith provided can support a better therapeutic approach to hypertension, tailored to patients with, or with high susceptibility to, psychiatric illness. It may prompt clinical studies exploring the potential benefit of antihypertensive drugs in selected patients with neuropsychiatric comorbidities that include outcomes of neuropsychiatric interest and specifically assess undesirable effects or interactions.
Proteomic and phosphoproteomic landscapes of acute myeloid leukemia
Authors: Michael H. Kramer, Qiang Zhang, Robert Sprung, Ryan B. Day, Petra Erdmann-Gilmore, Yang Li, Ziheng Xu, Nichole M. Helton, Daniel R. George, Yiling Mi, Peter Westervelt, Jacqueline E. Payton, Sai M. Ramakrishnan, Christopher A. Miller, Daniel C. Link, John F. DiPersio, Matthew J. Walter, R. Reid Townsend, Timothy J. Ley
Journal: Blood (2022)

Abstract We have developed a deep-scale proteome and phosphoproteome database from 44 representative acute myeloid leukemia (AML) patients from the LAML TCGA dataset and 6 healthy bone marrow–derived controls. After confirming data quality, we orthogonally validated several previously undescribed features of AML revealed by the proteomic data. We identified examples of posttranscriptionally regulated proteins both globally (ie, in all AML samples) and also in patients with recurrent AML driver mutations. For example, samples with IDH1/2 mutations displayed elevated levels of the 2-oxoglutarate–dependent histone demethylases KDM4A/B/C, despite no changes in messenger RNA levels for these genes; we confirmed this finding in vitro. In samples with NPMc mutations, we identified several nuclear importins with posttranscriptionally increased protein abundance and showed that they interact with NPMc but not wild-type NPM1. We identified 2 cell surface proteins (CD180 and MRC1/CD206) expressed on AML blasts of many patients (but not healthy CD34+ stem/progenitor cells) that could represent novel targets for immunologic therapies and confirmed these targets via flow cytometry. Finally, we detected nearly 30 000 phosphosites in these samples; globally, AML samples were associated with the abnormal phosphorylation of specific residues in PTPN11, STAT3, AKT1, and PRKCD. FLT3-TKD samples were associated with increased phosphorylation of activating tyrosines on the cytoplasmic Src-family tyrosine kinases FGR and HCK and related signaling proteins. PML-RARA–initiated AML samples displayed a unique phosphorylation signature, and TP53-mutant samples showed abundant phosphorylation of serine-183 on TP53 itself. This publicly available database will serve as a foundation for further investigations of protein dysregulation in AML pathogenesis.
Longitudinal trajectories in renal function before and after heart failure hospitalization among patients with heart failure with preserved ejection fraction in the <scp>PARAGON‐HF</scp> trial
Authors: Safia Chatur, Muthiah Vaduganathan, Alexander Peikert, Brian L. Claggett, Finnian R. McCausland, Hicham Skali, Marc A. Pfeffer, Iris E. Beldhuis, Lars Kober, Petar Seferovic, Martin Lefkowitz, John J.V. McMurray, Scott D. Solomon
Journal: European Journal of Heart Failure (2022)

Worsening renal function may impact long-term outcomes in heart failure (HF). However, little is known about the longitudinal trajectories in renal function in relation to HF hospitalization or how this high-risk clinical event impacts renal outcomes.In PARAGON-HF, we evaluated the association between recency of prior HF hospitalization (occurring pre-randomization) and subsequent first renal composite outcome: (i) time to ≥50% decline in estimated glomerular filtration rate (eGFR); (ii) development of end-stage renal disease; or (iii) death attributable to renal causes. A total of 2306 (48.1%) patients had a history of prior HF hospitalization. Incident rates of the renal outcome were highest in those most recently hospitalized and decreased with longer time from last hospitalization. Treatment effect on the renal outcome of sacubitril/valsartan versus valsartan was similar between patients with (hazard ratio [HR] 0.43; 95% confidence interval [CI] 0.24-0.76) and without (HR 0.63; 95% CI: 0.33-1.18; pinteraction = 0.39) a prior history of HF hospitalization and appeared consistent regardless of timing of prior hospitalization for HF (pinteraction = 0.39). Serial eGFR measurements leading up to and after a HF hospitalization (occurring during the study period) and estimated eGFR trajectories using repeated measures regression models with restricted cubic splines were also examined. Patients experiencing a post-randomization HF hospitalization had a significant decline in eGFR prior to hospitalization while patients without HF hospitalization experienced a relatively stable eGFR trajectory (p < 0.001). A change in the rate of decline of eGFR trajectory was observed 12 months preceding a HF hospitalization, and continued in the post-discharge window to 12 months following hospitalization.Heart failure hospitalization denotes increased risk for kidney disease progression which continues following recovery from HF decompensation in patients with HF with preserved ejection fraction.PARAGON-HF (Prospective Comparison of ARNI with ARB Global Outcomes in HF with Preserved Ejection Fraction), ClinicalTrials.gov NCT01920711.
Identification of robust deep neural network models of longitudinal clinical measurements
Authors: Hamed Javidi, Arshiya Mariam, Gholamreza Khademi, Emily C. Zabor, Ran Zhao, Tomas Radivoyevitch, Daniel M. Rotroff
Journal: npj Digital Medicine (2022)

Abstract Deep learning (DL) from electronic health records holds promise for disease prediction, but systematic methods for learning from simulated longitudinal clinical measurements have yet to be reported. We compared nine DL frameworks using simulated body mass index (BMI), glucose, and systolic blood pressure trajectories, independently isolated shape and magnitude changes, and evaluated model performance across various parameters (e.g., irregularity, missingness). Overall, discrimination based on variation in shape was more challenging than magnitude. Time-series forest-convolutional neural networks (TSF-CNN) and Gramian angular field(GAF)-CNN outperformed other approaches ( P &lt; 0.05) with overall area-under-the-curve (AUCs) of 0.93 for both models, and 0.92 and 0.89 for variation in magnitude and shape with up to 50% missing data. Furthermore, in a real-world assessment, the TSF-CNN model predicted T2D with AUCs reaching 0.72 using only BMI trajectories. In conclusion, we performed an extensive evaluation of DL approaches and identified robust modeling frameworks for disease prediction based on longitudinal clinical measurements.
Regaining adequate treatment responses in patients with psoriasis who discontinued dose reduction of adalimumab, etanercept or ustekinumab
Authors: Lara S. van der Schoot, Selma Atalay, Marisol E. Otero, Wietske Kievit, Juul M.P.A. van den Reek, Elke M.G.J. de Jong
Journal: British Journal of Dermatology (2022)

The presence of skin fragility in DEB reinforces the assumption that the rupture of the epidermal barrier observed in FD, which leads to an invasion of the subepidermal compartment by bacteria of transient flora, 1,2 is a major factor in FD.In hair follicles, the expression of BMZ components is similar to that of interfollicular epidermis in the upper and middle part, and decreases progressively in the lower part, with incomplete hemidesmosomes. 5,6 This transient region of the hair follicle during the hair cycle is then naturally more fragile.Constitutional anomalies of one of the proteins of the BMZ could increase this skin fragility and then favour FD in patients with EB.Of note, this transient region is also the less defended part of the hair follicle as a result of immune privilege. 7 This point suggests that in DEB, mechanical stress could promote the passage of pathogens present on the superficial part of the hair follicle toward its subepidermal part, whose immune defences are weaker.FD is more common in men, but most of the patients with FD/DEB in our cohort are women, even though the DEB sex ratio is 1.In the same way that hair loss in RDEB is worse in women who put their hair under tension, 5 the mechanical stress due to some women's habits of hairdressing with traction could lead more frequently to FD in those with DEB.Because many patients with DEB (76%) do not exhibit FD, factors additional to skin fragility are necessary to trigger FD.Interestingly, although skin fragility in DEB concerns the entire skin surface, chronic folliculitis leading to FD occurs mainly on the scalp, which suggests a scalp hair follicle-specific condition that could be linked to the specificity of the scalp microbiota.In support of this hypothesis, FD appears in patients with DEB and in those without DEB, only during or after puberty, a time during which the skin microbiota switches towards its final adult composition. 8 In conclusion, our findings imply that DEB, especially RDEB, predisposes to FD, and support the hypothesis that a skin barrier defect in the subepidermal part of the hair follicle contributes to the pathogenesis of FD.